Abnormal Food Timing and Circadian Dyssynchrony in Alcohol Induced Colon Carcinogenesis

酒精诱发结肠癌中的异常进食时间和昼夜节律不同步

• 批准号: 10166729
• 负责人: Faraz Bishehsari
• 金额: $ 18.9万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-10 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166729
• 关键词: Address; Admission activity; Alcohol consumption; Alcohols; Animal Experiments; Animal Model; Animals; Apoptosis; Area; Biological Rhythm; Bioperiodicity; Brain; Calories; Cancer Etiology; Cancerous; Cells; Chronic; Chronic Disease; Circadian Dysregulation; Circadian Rhythms; Collaborations; Colon; Colon Carcinoma; Colon Injury; Colorectal Cancer; Consumption; Cross-Over Trials; Data; Eating; Food; Gastrointestinal tract structure; Gene Expression; Genes; Genetic Predisposition to Disease; Habits; Homeostasis; Hour; Human; Immigration; Immune; Immune system; Individual; Inflammation; Inflammatory; Inherited; Intake; Intervention; Intestinal Mucosa; Intestines; Knowledge; Lead; Lesion; Life Style; Light; Link; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Measurement; Measures; Mediating; Melatonin; Modernization; Mucositis; Mucous Membrane; Neoplastic Processes; Oral mucous membrane structure; Organ; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pattern; Peripheral; Play; Precancerous Polyp; Predisposition; Process; Randomized; Recording of previous events; Regulatory T-Lymphocyte; Research; Risk; Risk Factors; Role; Salivary; Sampling; Scientist; Sigmoid colon; Sigmoidoscopy; Sleep; Societies; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Translating; Tubular Adenoma; Woman; adenoma; alcohol effect; alcohol intervention; cancer risk; carcinogenesis; circadian; circadian pacemaker; cofactor; colon carcinogenesis; colorectal cancer risk; colorectal cancer treatment; comparative; epidemiology study; feeding; food consumption; high risk; inflammatory disease of the intestine; inflammatory marker; men; microbiota; microbiota profiles; mortality; mouse model; neutrophil; novel; polyposis; preventive intervention; recruit; risk stratification; tissue injury; transcriptome sequencing; tumor; tumorigenic

Abstract Colorectal cancer (CRC) is the second leading cause of cancer mortality in the US. CRC's risk is closely linked to the modern lifestyle. Alcohol is commonly used in our society and is an established risk factor for both pre-cancerous (polyp) and cancerous lesions of the colon. However this knowledge has not been translated to our current risk stratifications for CRC as the process of alcohol-induced carcinogenesis is not predictable. Mucosal inflammation is a well-established mechanism that mediates the effect of alcohol induced tissue injury in the intestine. Inflammation also plays a crucial role in pathogenesis of CRC. Factors that promote a pro-tumorigenic inflammatory state in the setting of alcohol are unknown. Since CRC occurs only in a small subset of alcohol users, alcohol alone may not be sufficient to start the neoplastic process and additional cofactors are required. One such factor is circadian dysrhythmia that is another modern lifestyle habit, shown to be associated with an increased risk of CRC. Further, we have shown that disruption of circadian rhythm exacerbates alcohol-induced intestinal inflammation. We hypothesize that altered circadian rhythms due to “wrong-time” eating (abnormal eating) are an important determinant in alcohol induced intestinal mucosal inflammation and carcinogenesis. Our preliminary data supports our hypothesis and shows that abnormal eating patterns accelerate alcohol-induced polyposis in a mouse model of CRC. In Aim 1, we will establish the inflammatory profiles associated with alcohol ± abnormal eating patterns in the tissues collected from our animal experiments. Here, we establish a cancer-promoting inflammatory state in the colon, determined by RNA-seq and calibrated by immunostaining, linked to alcohol or abnormal eating patterns or their combination. We will then determine the effect of alcohol ± delayed eating patterns (4 conditions) in humans on central and peripheral circadian rhythms in Aim 2, and colon carcinogenesis and mucosal markers in Aim 3. After each intervention, subjects will undergo (1) assessment of central circadian rhythm measured by the dim light melatonin onset (DLMO); (2) assessment of intestinal circadian rhythm measured by clock gene expression in buccal mucosal cells; and (3) sigmoidoscopy sampling of the colon mucosa to assess inflammatory and carcinogenesis markers as well as microbiota. This proposal will identify delayed eating as a promoting factor for alcohol-induced colon injury leading to carcinogenesis, and will provide a paradigm shift in our understanding of the mechanisms underlying alcohol cancer promoting effects, as well as risk stratification of alcohol drinkers.

抽象的 结直肠癌（CRC）是美国癌症死亡率的第二大原因。 CRC的风险是 与现代生活方式密切相关。酒精是在我们的社会中常用的，是既定风险因素 对于结肠前癌前（息肉）和取消病变。但是这些知识不是 转化为我们目前对CRC的风险分层，因为酒精引起的致癌过程不是 可预测。粘膜注射是一种完善的机制，可介导酒精诱导的作用 肠损伤。炎症在CRC的发病机理中也起着至关重要的作用。因素 在酒精环境中促进促肿瘤炎症状态是未知的。由于CRC仅出现在 一小部分酒精使用者，仅酒精可能不足以开始肿瘤过程和 需要其他辅助因子。一个这样的因素是昼夜节律缺乏症，这是另一种现代生活方式 习惯，与CRC风险增加有关。此外，我们已经证明了这一中断 昼夜节律加剧了酒精引起的肠道炎症。我们假设改变了昼夜节律 由于“时间错误”饮食（异常饮食）引起的节奏是酒精诱导的重要的 肠粘膜注射和致癌作用。我们的初步数据支持我们的假设，并显示 在CRC的小鼠模型中，这种异常的饮食模式会加速酒精诱导的息肉病。在AIM 1中，我们将 在收集的组织中建立与酒精±异常饮食模式相关的炎症特征 从我们的动物实验。在这里，我们在结肠上建立了促进癌症的炎症状态， 由RNA-seq确定，并通过免疫染色，与酒精或异常饮食模式相关或 他们的组合。然后，我们将确定酒精±延迟饮食模式的影响（4个条件） AIM 2中的中央和周围昼夜节律的人类，结肠癌和粘膜标记 在AIM 3中。每次干预后，受试者将经历（1）测量中央昼夜节律的评估 通过昏暗的褪黑激素发作（DLMO）； （2）评估按时钟测得的肠道节奏 颊粘膜细胞中的基因表达； （3）结肠粘膜的乙状结肠镜检查以评估 炎症和癌变标志物以及微生物群。该建议将确定延迟的饮食是 促进酒精引起的结肠损伤导致癌变的因子，并将提供范式转移 我们对酒精癌促进效果的机制以及风险分层的理解 喝酒的人。